TNF is produced by macrophages and mononuclear phagocytes. It is cytotoxic or cytostatic for a broad range of animal and human cancer cells in vitro and induces hemorrhagic necrosis in certain animal tumors and heterotransplanted human tumors in vivo [K. Haranaka and N. Satomi, "Note: Cytotoxic Activity of Tumor Necrosis Factor (TNF) on Human Cancer Cells in vitro", Japan J. Exp. Med., 51, pp. 191-94 (1981); L. Old, "Cancer Immunology: The Search for Specificity-- G.H.A. Clowes Memorial Lecture", Cancer Research, 41, pp. 361-75 (1981)].
Compounds displaying TNF activity have been obtained from sera of mice and rabbits that have been infected with Bacillus-Calmette-Guerin (BCG) or Corynebacterium and treated with lipopoly-saccharide (LPS) of Escherichia coli [E. A. Carswell et al., "An Endotoxin-Induced Serum Factor That Causes Necrosis Of Tumors", Proc. Natl. Acad. Sci. USA, 72, pp. 3666-70 (1975)]. They have also been derived from the incubation media of macrophage-enriched peritoneal exudate cells of mice infected with BCG, as well as from macrophage-like tumor cells (PU5-1.8) and peritoneal macrophages of pretreated mice, which have been propagated in vitro with macrophage growth factor and stimulated with LPS [D. Mannel, R. Moore and S. Mergenhagen, "Macrophages as a Source of Tumoricidal Activity (Tumor Necrotizing Factor)", Infect. Immun., 30, pp. 523-30 (1980)].
Furthermore, when human monocytes, which are macrophage precursors, are isolated, for example, from the blood of healthy human donors, and are stimulated with lymphokines and/or LPS, they produce chemical agents having cytotoxic or cytostatic effects on murine target cells and human transformed cells [N. Matthews, "Production of an Anti-tumour Cytotoxin by Human Monocytes: Comparison of Endotoxin, Interferons and Other Agents as Inducers", Br. J. Cancer, 45, pp. 615-17 (1982); J. Hammerstrom, "Soluble Cytostatic Factor(s) Released from Human Monocytes: I. Production and Effect on Normal and Transformed Human Target Cells", Scand. J. Immunol., 15, pp. 311-18 (1982)]. Accordingly, as TNF is produced (after appropriate treatment) by monocyte-derived cells, the substance is sometimes referred to as "monocyte cytotoxin" [D. S. Stone-Wolf et al., "Interrelationships Of Human Interferon-Gamma With Lymphotoxin And Human Cytotoxin", J. Exp. Med., 159, pp. 820-43 (1984)].
A fraction of the .alpha..sub.1 -.alpha..sub.2 globulins from the serum of normal humans has also been shown to be toxic to tumors in mice and to inhibit the growth in vitro of human colon cancer, melanoma and neuroblastoma cell lines [U.S. Pat. No. 4,309,418; S. Green et al., Cancer Letters, 6, pp. 235-40 (1979); J. Cell. Biol., 79, p. 67 (1978)].
However, at present, animal and human TNFs have been produced only in extremely small quantities. The processes for the production of animal TNFs entail either sacrificing large numbers of pretreated mice or rabbits and purifying their sera to recover the TNFs or collecting their macrophages, stimulating the cells in vitro and recovering and purifying the produced TNFs from the supernatant. The collection of cells from human donors for in vitro incubation to produce TNFs and the purification of the .alpha.-globulin fraction of serum from human donors to recover the anti-tumor agents are, likewise, not useful on a large scale. Furthermore, all of these procedures are time-consuming, expensive, and provide very low yields of TNF.